title: Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and IP3R activity in muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyclosporine A (CsA) reduces muscle degeneration at low dose and acts, at least in part, through a mitochondrial cyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation through cyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrial fragmentation not only in dystrophic nematodes, but also in a zebrafish model for DMD. This abnormal mitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, we demonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promoting gene drp-1 reduces muscle degeneration and improves locomotion abilities of dystrophic nematodes. Further experiments revealed that cytochrome c is involved in muscle degeneration in C. elegans and seems to act, at least in part, through an interaction with the inositol trisphosphate receptor calcium channel, ITR-1. Altogether, our findings reveal that mitochondria play a key role in the early process of muscle degeneration and may be a target of choice for the design of novel therapeutics for DMD. In addition, our results provide the first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochrome c can act in cell death.
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School, University of Sydney, NSW 2050, Australia.
authors.forename: Jean
authors.initials: J
authors.lastname: Giacomotto
authors.forename: Nicolas
authors.initials: N
authors.lastname: Brouilly
authors.forename: Ludivine
authors.initials: L
authors.lastname: Walter
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Mariol
authors.forename: Joachim
authors.initials: J
authors.lastname: Berger
authors.forename: Laurent
authors.initials: L
authors.lastname: Ségalat
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
authors.forename: Peter D
authors.initials: PD
authors.lastname: Currie
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gieseler
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008704:Methazolamide / Q000494:pharmacology; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010802:Phylogeny; D017385:Sequence Homology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D024101:Mitochondrial Proteins; D016572:Cyclosporine; D045304:Cytochromes c; D021983:Cyclophilins; D008704:Methazolamide